1. Field of the Invention
The present invention relates to sodium channel blockers. The present invention also includes a variety of methods of treatment using these inventive sodium channel blockers, their pharmaceutically acceptable salt forms, which are useful as sodium channel blockers, compositions containing the same, therapeutic methods including but not limited to treating dry eye, treating Sjogren's disease-associated dry eye, promoting ocular hydration, promoting corneal hydration and the treatment of other mucosal diseases and uses for the same and processes for preparing the same. The present invention also relates to novel compounds for the treatment of dry eye, particularly including (2R,2′R)—N,N′-(3,3′-(2-(4-(4-(3-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino)butyl)phenoxy)ethylazanediyl)bis(propane-3,1-diyl))bis(2-amino-6-guanidinohexanamide) and its pharmaceutically acceptable salt forms, which are useful as sodium channel blockers, compositions containing the same, therapeutic methods including but not limited to treating dry eye, treating Sjogren's disease-associated dry eye, promoting ocular hydration, promoting corneal hydration and the treatment of other mucosal diseases and uses for the same and processes for preparing the same.
2. Description of the Background
The mucosal epithelial cells at the interface between the environment and the body have evolved a number of “innate defenses”, i.e., protective mechanisms. A principal function of such innate defense is to cleanse these surfaces from microorganisms, particles and other foreign material. This process requires the presence of a layer of liquid to propel these microorganisms, particles and other foreign material away from the body to avoid colonization of microorganisms and/or tissue damage. Typically, the quantity of the liquid layer on a mucosal surface reflects the balance between epithelial liquid secretion, often reflecting anion (Cl− and/or HCO3−) secretion coupled with water (and a cation counter-ion), and epithelial liquid absorption, often reflecting Na+ absorption, coupled with water and counter anion (Cl− and/or HCO3−). Many diseases of mucosal surfaces are caused by too little protective liquid on those mucosal surfaces created by an imbalance between secretion (too little) and absorption (relatively too much). The critical salt transport processes that characterize a number of mucosal dysfunctions resides in the epithelial layer of the mucosal surface.
Chronic dry eye disease, also known as keratoconjunctivitis sicca, is one of the most frequently diagnosed ocular diseases, affecting more than 5 million people in the United States alone. Dry eye is characterized by inadequate aqueous tear fluid on the eyes, resulting in painful irritation, inflammation on the ocular surface, and impaired vision, and is caused by failure of lacrimal glands to secrete liquid in the face of continued Na+ dependent liquid absorption on conjunctival surfaces. Dry eye is a multi-factorial disease, resulting from a common etiology of insufficient tear film, causing ocular surface damage and symptoms of ocular discomfort.
The few current therapies available, which include both immunosuppressive agents and over-the-counter tear replacements, are not sufficiently efficacious for many users or only provide transient relief from dry eye symptoms. The dry eye market is dominated by over-the-counter (OTC) tear replacements or artificial tears, estimated to be used by ˜80% of dry eye patients. Artificial tears provide immediate symptomatic relief from the sensation of ocular burning and irritation by adding liquid to the ocular surface. Yet, the benefits from artificial tears are short-lived as the fluid drops are rapidly cleared from the ocular surface, providing, at most, palliative relief and requiring frequent application throughout the day.
While individuals with dry eye may not exhibit overt ocular inflammation such as red, inflamed eyes, chronic ocular inflammation is now well recognized as a significant factor perpetuating the chronic cycle of dry eye. The one approved prescription drug for the treatment of chronic dry eye is Restasis® (0.05% Cyclosporine A emulsion, Allergan), which is marketed to increase tear output “in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca.” In a six month, Phase 3 pivotal trial in subjects with dry eye, Restasis statistically increased tear volume (assessed by Schirmer wetting) in 15% of the treated individuals, compared to 5% on vehicle. While the mechanism of Restasis is not fully understood, it is speculated that the inhibition of chronic ocular inflammation may, over time, restore corneal sensitivity and improve reflex tearing. However, Restasis has a low responder rate, a 3 month delay for full therapeutic benefit, and side effects, such as burning on application.
Therefore, the development of novel hydrating agents to treat dry eye would be of tremendous benefit to the therapeutic milieu. The volume of tear film on the ocular surface represents a balance between tear fluid output versus fluid loss via drainage, evaporation, or epithelial absorption. Similar to other epithelial tissues, the epithelium of the conjunctiva and cornea are capable of regulating the hydration status of the mucosal surface through active salt and water transport.
One approach to replenish the protective liquid layer on mucosal surfaces is to “re-balance” the system by blocking Na+ channel and liquid absorption. The epithelial protein that mediates the rate-limiting step of Na+ and liquid absorption is the epithelial Na+ channel (ENaC) and is a key regulator of sodium (and water) absorption in numerous tissues, including the eye. ENaC is expressed on the apical surface of the corneal and conjunctival epithelia in rodents, larger mammals, and man where it functions as a critical pathway for sodium (and water) absorption (Krueger B, Schlötzer-Schrehardt U, Haerteis S, Zenkel M, Chankiewitz V E, Amann K U, Kruse F E, Korbmacher C. Four subunits (αβγδ) of the epithelial sodium channel (ENaC) are expressed in the human eye in various locations. Invest Ophthalmol V is Sci. 2012; 53(2):596-604).
In a series of in vivo bioelectric studies, Levin et al. (Levin M H, Kim J K, Hu J, Verkman
A S. Potential difference measurements of ocular surface Na+ absorption analyzed using an electrokinetic model. Invest Opthalmol V is Sci. 2006; 47(1):306-16) confirmed ENaC-mediated sodium transport is a substantial contributor to the ocular surface electrical potential difference Furthermore, the topical addition of the ENaC blocker amiloride produced an approximate doubling of tear volume that remained elevated for >60 minutes post-administration in rats (Yu D, Thelin W R, Rogers T D, Stutts M J, Randell S H, Grubb B R, Boucher R C. Regional differences in rat conjunctival ion transport activities. Am J Physiol Cell Physiol. 2012; 303(7):C767-80.) and rabbits (Hara S, Hazama A, Miyake M, Kojima T, Sasaki Y, Shimazaki J, Dogru M and Tsubota K. The Effect of Topical Amiloride Eye Drops on Tear Quantity in Rabbits. Molecular Vision 2010; 16:2279-2285).
Taken together, these data provide an important proof-of-concept that the inhibition of ENaC will increase tear volume. The inhibition of ENaC in the eye is predicted to preserve lacrimal secretions and maintain hydration on the ocular surface. Because ENaC is positioned on the apical surface of the epithelium, i.e. the mucosal surface-environmental interface, to inhibit ENaC mediated Na+ and liquid absorption, an ENaC blocker of the amiloride class (which blocks from the extracellular domain of ENaC) must be delivered to the mucosal surface and, importantly, be maintained at this site, to achieve therapeutic utility. The present invention describes diseases characterized by too little liquid on mucosal surfaces and “topical” sodium channel blockers designed to exhibit the increased potency, reduced mucosal absorption, and slow dissociation (“unbinding” or detachment) from ENaC required for therapy of these diseases.
The use of ENaC blockers has been reported for a variety of diseases which are ameliorated by increased mucosal hydration. In particular, the use of ENaC blockers in the treatment of respiratory diseases such as chronic bronchitis (CB), cystic fibrosis (CF), and COPD, which reflect the body's failure to clear mucus normally from the lungs and ultimately result in chronic airway infection, has been reported. See, Evidence for airway surface dehydration as the initiating event in CF airway disease, R. C. Boucher, Journal of Internal Medicine, Vol. 261, Issue 1, January 2007, pages 5-16; and Cystic fibrosis: a disease of vulnerability to airway surface dehydration, R. C. Boucher, Trends in Molecular Medicine, Vol. 13, Issue 6, June 2007, pages 231-240.
Data indicate that the initiating problem in both chronic bronchitis and cystic fibrosis is the failure to clear mucus from airway surfaces. The failure to clear mucus reflects an imbalance in the quantities of mucus as airway surface liquid (ASL) on airway surfaces. This imbalance results in a relative reduction in ASL which leads to mucus concentration, reduction in the lubricant activity of the periciliary liquid (PCL), mucus adherence to the airway surface, and failure to clear mucus via ciliary activity to the mouth. The reduction in mucus clearance leads to chronic bacterial colonization of mucus adherent to airway surfaces. The chronic retention of bacteria, inability of local antimicrobial substances to kill mucus-entrapped bacteria on a chronic basis, and the consequent chronic inflammatory response to this type of surface infection, are manifest in chronic bronchitis and cystic fibrosis.
Chronic obstructive pulmonary diseases are characterized by dehydration of airway surfaces and the retention of mucous secretions in the lungs. Examples of such diseases include cystic fibrosis, chronic bronchitis, and primary or secondary ciliary dyskinesia. Such diseases affect approximately 15 million patients in the United States, and are the sixth leading cause of death. Other airway or pulmonary diseases characterized by the accumulation of retained mucous secretions include sinusitis (an inflammation of the paranasal sinuses associated with upper respiratory infection) and pneumonia.
Chronic bronchitis (CB), including the most common lethal genetic form of chronic bronchitis, cystic fibrosis (CF), are diseases that reflect the body's failure to clear mucus normally from the lungs, which ultimately produces chronic airways infection. In the normal lung, the primary defense against chronic intrapulmonary airways infection (chronic bronchitis) is mediated by the continuous clearance of mucus from bronchial airway surfaces. This function in health effectively removes from the lung potentially noxious toxins and pathogens. Recent data indicate that the initiating problem, i.e., the “basic defect,” in both CB and CF is the failure to clear mucus from airway surfaces. The failure to clear mucus reflects an imbalance between the amount of liquid and mucin on airway surfaces. This “airway surface liquid” (ASL) is primarily composed of salt and water in proportions similar to plasma (i.e., isotonic). Mucin macromolecules organize into a well-defined “mucus layer” which normally traps inhaled bacteria and is transported out of the lung via the actions of cilia which beat in a watery, low viscosity solution termed the “periciliary liquid” (PCL). In the disease state, there is an imbalance in the quantities of mucus as ASL on airway surfaces. This results in a relative reduction in ASL which leads to mucus concentration, reduction in the lubricant activity of the PCL, and a failure to clear mucus via ciliary activity to the mouth. The reduction in mechanical clearance of mucus from the lung leads to chronic bacterial colonization of mucus adherent to airway surfaces. It is the chronic retention of bacteria, the failure of local antimicrobial substances to kill mucus-entrapped bacteria on a chronic basis, and the consequent chronic inflammatory responses of the body to this type of surface infection, that lead to the syndromes of CB and CF.
The current afflicted population in the U.S. is 12,000,000 patients with the acquired (primarily from cigarette smoke exposure) form of chronic bronchitis and approximately 30,000 patients with the genetic form, cystic fibrosis. Approximately equal numbers of both populations are present in Europe. In Asia, there is little CF but the incidence of CB is high and, like the rest of the world, is increasing.
There is currently a large, unmet medical need for products that specifically treat CB and CF at the level of the basic defect that cause these diseases. The current therapies for chronic bronchitis and cystic fibrosis focus on treating the symptoms and/or the late effects of these diseases. Thus, for chronic bronchitis, β-agonists, inhaled steroids, anti-cholinergic agents, and oral theophyllines and phosphodiesterase inhibitors are all in development. However, none of these drugs treat effectively the fundamental problem of the failure to clear mucus from the lung. Similarly, in cystic fibrosis, the same spectrum of pharmacologic agents is used. These strategies have been complemented by more recent strategies designed to clear the CF lung of the DNA (“Pulmozyme”; Genentech) that has been deposited in the lung by neutrophils that have futilely attempted to kill the bacteria that grow in adherent mucus masses and through the use of inhaled antibiotics (“TOBI”) designed to augment the lungs' own killing mechanisms to rid the adherent mucus plaques of bacteria. A general principle of the body is that if the initiating lesion is not treated, in this case mucus retention/obstruction, bacterial infections became chronic and increasingly refractory to antimicrobial therapy. Thus, a major unmet therapeutic need for both CB and CF lung diseases is an effective means of re-hydrating airway mucus (i.e., restoring/expanding the volume of the ASL) and promoting its clearance, with bacteria, from the lung.
R. C. Boucher, in U.S. Pat. No. 6,264,975, describes the use of pyrazinoylguanidine sodium channel blockers for hydrating mucosal surfaces. These compounds, typified by the well-known diuretics amiloride, benzamil, and phenamil, are effective. However, these compounds suffer from the significant disadvantage that they are (1) relatively impotent, which is important because the mass of drug that can be inhaled by the lung is limited; (2) rapidly absorbed, which limits the half-life of the drug on the mucosal surface; and (3) are freely dissociable from ENaC. The sum of these disadvantages embodied in these well-known diuretics produces compounds with insufficient potency and/or effective half-life on mucosal surfaces to have therapeutic benefit for hydrating mucosal surfaces.
R. C. Boucher, in U.S. Pat. No. 6,926,911, suggests the use of the relatively impotent sodium channel blockers such as amiloride, with osmolytes for the treatment of airway diseases. This combination gives no practical advantage over either treatment alone and is clinically not useful (see Donaldson et al, N Eng J Med 2006; 353:241-250). Amiloride was found to block the water permeability of airways and negate the potential benefit of concurrent use of hypertonic saline and amiloride.
U.S. Pat. No. 5,817,028 to Anderson describes a method for the provocation of air passage narrowing (for evaluating susceptibility to asthma) and/or the induction of sputum in subjects via the inhalation of mannitol. It is suggested that the same technique can be used to induce sputum and promote mucociliary clearance. Substances suggested include sodium chloride, potassium chloride, mannitol and dextrose.
Clearly, what is needed are drugs that are more effective at restoring the clearance of mucus from the lungs of patients with CB/CF. The value of these new therapies will be reflected in improvements in the quality and duration of life for both the CF and the CB populations.
Other mucosal surfaces in and on the body exhibit subtle differences in the normal physiology of the protective surface liquids on their surfaces but the pathophysiology of disease reflects a common theme, i.e., too little protective surface liquid. For example, in xerostomia (dry mouth) the oral cavity is depleted of liquid due to a failure of the parotid sublingual and submandibular glands to secrete liquid despite continued Na+ (ENaC) transport mediated liquid absorption from the oral cavity.
In rhinosinusitis, there is an imbalance, as in CB, between mucin secretion and relative ASL depletion. Finally, in the gastrointestinal tract, failure to secrete Cl— (and liquid) in the proximal small intestine, combined with increased Na+ (and liquid) absorption in the terminal ileum leads to the distal intestinal obstruction syndrome (DIOS). In older patients excessive Na+ (and volume) absorption in the descending colon produces constipation and diverticulitis.
The published literature includes a number of patent applications and granted patents to Parion Sciences Inc., directed toward pyrazinoylguanidine analogs as sodium channel blockers. Examples of such publications include PCT Publication Nos. WO2007146867, WO2003/070182, WO2003/070184, WO2004/073629, WO2005/025496, WO2005/016879, WO2005/018644, WO2006/022935, WO2006/023573, WO2006/023617, WO2007/018640, WO2007146870, WO2007/146869, WO2008030217, WO2008/031028, WO2008/031048, WO2013/003386, WO2013/003444, and U.S. Pat. Nos. 6,858,614, 6,858,615, 6,903,105, 6,995,160, 7,026,325, 7,030,117, 7,064,129, 7,186,833, 7,189,719, 7,192,958, 7,192,959, 7,192,960, 7,241,766, 7,247,636, 7,247,637, 7,317,013, 7,332,496, 7,368,447, 7,368,450, 7,368,451, 7,375,102, 7,375,107, 7,388,013, 7,399,766, 7,410,968, 7,807,834, 7,820,678, 7,842,697, 7,868,010, 7,956,059, 7,981,898, 8,008,494, 8,022,210, 8,058,278, 8,124,607, 8,143,256, 8,163,758, 8,198,286, 8,211,895, 8,198,286, 8,227,474, and 8,324,218.
There remains a need for novel sodium channel blocking compounds with enhanced potency and effectiveness on mucosal tissues, especially ocular tissues. There also remains the need for novel sodium channel blocking compounds that provide therapeutic effect, but minimize or eliminate the onset or progression of hyperkalemia in recipients.